High body weight is associated with increased risk for hypertension, dyslipidemia, inflammation, metabolic syndrome, stroke, and coronary heart disease. While exercise is commonly cited as an important tool for weight reduction, numerous studies have demonstrated that: 1) exercise training without a dietary intervention results in far less weight loss than expected given the expended calories and this is most evident when the exercise dose is large (e 60 minutes per day), and 2) the weight loss response to exercise is very heterogeneous. Nevertheless, most weight management guidelines recommend an hour or more a day of exercise both for promoting weight loss and preventing weight regain after loss. There is clearly a need to identify the mechanisms responsible for the failure of exercise to produce substantial weight loss in most but not all individuals, as having a better understanding of the mechanisms responsible for this phenomenon is critical to developing strategies to counter it. The leading mechanisms include exercise-induced increases in energy intake, decreases in resting metabolic rate (adjusted for change in body mass), and decreases in non- exercise activity levels. The purpose of the E-MECHANIC Trial is to compare the effect of two doses of exercise on energy intake and body weight. The exercise doses will reflect current recommendations for: 1) general health (~800- 1000 kcal/week), and 2) weight loss and maintenance of weight loss (~2000 to 2500 kcal/week). The exercise groups will not be provided with a dietary intervention, and the study also includes a non-exercise control group. The primary outcome variables are energy intake and the discrepancy between expected weight loss and observed weight loss (Wt. Lossdif). Energy intake will be measured using two state-of-the-art methods: doubly labeled water and laboratory-based food intake tests. Energy intake was chosen as the primary outcome variable and the most likely compensatory mechanism that limits exercise-induced weight loss, but change in metabolism (resting metabolic rate adjusted for change in body composition) and activity levels (excluding structured exercise) will also be evaluated as possible compensatory mechanisms and secondary outcome variables. Lastly, in an effort to guide the development of interventions to combat compensation, we will behaviorally phenotype participants to characterize those who do and do not compensate by increasing energy intake. The results of the study will provide important information for health and weight loss recommendations, and identify ways to counter compensatory mechanisms that limit exercise-induced weight loss. PUBLIC HEALTH RELEVANCE: Excess body weight is a significant risk factor for cardiovascular disease. Exercise is recommended for weight reduction, yet exercise training without a dietary intervention results in far less weight loss than expected given the expended calories and this is most evident when the exercise dose is large (e 60 minutes per day). In addition, the weight loss response to exercise is very heterogeneous. There is a need to identify the mechanisms responsible for the failure of exercise to produce substantial weight loss in most but not all individuals, as having a better understanding of the mechanisms responsible for this phenomenon is critical to developing strategies to counter it. The purpose of the proposed research is to identify the mechanisms responsible for the failure of exercise to promote the expected amount of weight loss. Specifically, the study will determine if exercise results in increased energy intake, decreased resting metabolic rate (adjusted for change in body mass), and/or decreased non-exercise activity levels, which compensate for the energy deficit caused by exercise and limit weight loss. The results of the study will provide important information for weight loss recommendations and the development of interventions to combat compensation.